1. Human Embryology: Heart Development II Kimara L. Targoff, M.D. Division of Pediatric Cardiology, Columbia University Medical Center Developmental Genetics Program, Skirball Institute, NYU School of Medicine

2. Human Vascular Development Overview Aortic Arch Development Arterial Vascular Development Venous System Development Lymphatic Development Transition from Fetal to Post-Natal Circulation

3. Development of the Arterial and Venous Systems

4. Cranial Ends of the Dorsal Aortae Form a Dorsoventral Loop: The First Aortic Arch

5. Aortic Arches Arise in a Craniocaudal Sequence Surrounding the Pharynx

6. Aortic Arches Give Rise to Important Head, Neck, and Upper Thorax Vessels

7. Aortic Arch Development in the Chick Embryo

8. Fgf8 is Required for Pharyngeal Arch Development in Mouse Abu-Issa, R. et al., Development 2002.

9. Cardiovascular and Thymic Defects in Tbx1 Hypomorphic Mutant Neonates Hu, T. et al., Development 2004.

10. Aortic Arch Development 1 2 3 6 4 5 7 iseg Ventral aorta Dorsal aorta Harsh Thaker

11. Aortic Arch Development 1 2 3 6 4 5 7 iseg Ventral aorta Dorsal aorta Harsh Thaker

12. 6 3 3 4 4 7 iseg Aortic sac Truncus arteriosus 6 Aortic Arch and Derivatives Harsh Thaker

13. 6 3 3 4 4 7 iseg Harsh Thaker Aortic Arch and Derivatives

14. 6 3 3 4 4 7 iseg Aortic Arch and Derivatives Harsh Thaker

15. LCC RCC RSC BCA LSC DA Aortic Arch and Derivatives Harsh Thaker

16. LCC RCC RSC BCA LSC DA Recurrent Laryngeal Nerves Harsh Thaker

17. Defects in Normal Regression of the Arterial System Lead to Vascular Anomalies Double Aortic Arch – Failure of the right dorsal aorta to regress Aberrant Right Subclavian Artery – Regression of the right fourth arch – 1% of the general population – 40% of patients with Trisomy 21 and CHD Right Aortic Arch – Retention of the right dorsal aorta segment – 13-35% of patients with TOF – 8% of patients with TGA Double Aortic Arch – Failure of the right dorsal aorta to regress Aberrant Right Subclavian Artery – Regression of the right fourth arch – 1% of the general population – 40% of patients with Trisomy 21 and CHD Right Aortic Arch – Retention of the right dorsal aorta segment – 13-35% of patients with TOF – 8% of patients with TGA

18. Failure of Regression of the Right Dorsal Aorta Leads to a Double Aortic Arch

19. Double Aortic Arch 1 2 3 6 4 5 7 iseg Ventral aorta Dorsal aorta Harsh Thaker

20. Regression of the Right Fourth Arch Results in an Aberrant Right Subclavian Artery

21. Aberrant Right Subclavian Artery 1 2 3 6 4 5 7 iseg Ventral aorta Dorsal aorta Harsh Thaker

22. LCC RCC RSC BCA LSC DA Harsh Thaker Aberrant Right Subclavian Artery

23. Retention of the Right Dorsal Aortic Segment Yields a Right Aortic Arch

24. Right Aortic Arch 1 2 3 6 4 5 7 iseg Ventral aorta Dorsal aorta Harsh Thaker

25. Right Aortic Arch: Mirror Image Branching versus Aberrant Left Subclavian Artery

26. Vascular Rings May Cause Compression of the Trachea and the Esophagus Double Aortic Arch – Failure of the right dorsal aorta to regress Right Aortic Arch – Ductus arteriosus is directed towards the right – If the ductus, or later, the ligamentum arteriosum, passes behind the esophagus, constriction may occur Double Aortic Arch – Failure of the right dorsal aorta to regress Right Aortic Arch – Ductus arteriosus is directed towards the right – If the ductus, or later, the ligamentum arteriosum, passes behind the esophagus, constriction may occur

27. Double Aortic Arch Presenting with Dysphagia in a 31-Year-Old Woman

28. Aortic Arch Anomalies Can Cause Significant Clinically Compromise in the Neonatal Period Interrupted Aortic Arch – Obliteration of the right and left fourth aortic arches Coarctation of the Aorta – Constriction of the aorta in the region of the ductus arteriosus – 0.3% of live births – Most common cardiac anomaly in Turner’s Syndrome Interrupted Aortic Arch – Obliteration of the right and left fourth aortic arches Coarctation of the Aorta – Constriction of the aorta in the region of the ductus arteriosus – 0.3% of live births – Most common cardiac anomaly in Turner’s Syndrome

29. Obliteration of the Right and Left Fourth Aortic A r c h e s L e a d s t o a n A o r t i c A r c h I n t e r r u p t i o n Obliteration of the Right and Left Fourth Aortic Arches Leads to Interruption of the Aorta

30. Constriction of the Aorta in the Region of the Ductus Arteriosus Produces Coarctation

31. Post-ductal Coarctation of the Aorta Utilizes Collateral Circulation to Supply Blood to the Lower Body

33. Vitelline Arteries Give Rise to the Arterial Supply of the Gastrointestinal Tract

34. Lateral Branches of the Descending Aorta Highlight Developmental Histories of Each Organ

35. Umbilical Vitelline The Developing Venous System Sinus Venosus Cardinal Harsh Thaker

36. Vitelline Veins Form a Portal System to Drain Blood from the Foregut, Midgut, and Part of the Anorectal Canal

37. Umbilical Vitelline The Developing Venous System Sinus Venosus Cardinal Harsh Thaker Subcardinal Supra cardinal Supra-Subcardinal Anastomosis

38. The Systemic Venous System Develops from Four Bilaterally Symmetric Cardinal Veins

39. Following Remodeling of the Subcardinal System, the Supracardinal Veins Sprout

40. Remodeling of Abdominal Venous System Occurs through Obliteration of the Left Supracardinal Vein

41. Failure of Left Cardinal Veins to Undergo Normal Regression Leads to Venous Anomalies LSVC occurs in 0.3% to 0.5% of the normal population In 65% of cases, left brachiocephalic vein is also missing 4% of patients with CHD have an LSVC Usually drains to the coronary sinus LSVC occurs in 0.3% to 0.5% of the normal population In 65% of cases, left brachiocephalic vein is also missing 4% of patients with CHD have an LSVC Usually drains to the coronary sinus

42. Lymph Sacs and Ducts Form by Lymphangiogenesis to Drain Fluid from Tissue Spaces Throughout the Body

43. Cystic Hygromas Develop in Turner’s Syndrome Patients Secondary to Blockage of Lymphatic Ducts

44. Fetal Circulation Bypasses the Developing Pulmonary Circulation

45. Pulmonary Vascular Resistance Drops Precipitously and Initiates the Transition to Post-Natal Circulation

46. Normal Closure of the Ductus Arteriosus Occurs during the Transition to Neonatal Circulation in Series Prostaglandins maintain a patent ductus arteriosus Indomethacin is used to induce ductal closure Physiologic closure occurs by 2 days in 82% of patients Prostaglandins maintain a patent ductus arteriosus Indomethacin is used to induce ductal closure Physiologic closure occurs by 2 days in 82% of patients